The 2023 Orthopaedic Research Society's International Consensus Meeting on musculoskeletal infection: Summary from the host immunity section.

Musculoskeletal infections (MSKI), which are a major problem in orthopedics, occur when the pathogen eludes or overwhelms the host immune system. While effective vaccines and immunotherapies to prevent and treat MSKI should be possible, fundamental knowledge gaps in our understanding of protective, nonprotective, and pathogenic host immunity are prohibitive. We also lack critical knowledge of how host immunity is affected by the microbiome, implants, prior infection, nutrition, antibiotics, and concomitant therapies, autoimmunity, and other comorbidities. To define our current knowledge of these critical topics, a Host Immunity Section of the 2023 Orthopaedic Research Society MSKI International Consensus Meeting (ICM) proposed 78 questions. Systematic reviews were performed on 15 of these questions, upon which recommendations with level of evidence were voted on by the 72 ICM delegates, and another 12 questions were voted on with a recommendation of "Unknown" without systematic reviews. Two questions were transferred to another ICM Section, and the other 45 were tabled for future consideration due to limitations of available human resources. Here we report the results of the voting with internet access to the questions, recommendations, and rationale from the systematic reviews. Eighteen questions received a consensus vote of ≥90%, while nine recommendations failed to achieve this threshold. Commentary on why consensus was not achieved on these questions and potential ways forward are provided to stimulate specific funding mechanisms and research on these critical MSKI host defense questions.

A return to responsibility: A critique of the single actor strategic model of CSR.

Any functional utility gained through corporate social responsibility (CSR) depends on "responsibility" as the governing principle between "corporate" and "social" interests. We argue that Porter and Kramer's highly popularised notion of "shared value" has been pivotal to the erosion of responsibility as a moderating concept in CSR. Under this approach, "strategic" CSR becomes an instrument to leverage corporate advantage, rather than fulfil social responsibilities and address business-related harms. In mining, this approach has supported shallow, derivative ideas including the wellknown CSR artefact: "social license to operate" (SLTO). We argue that CSR, and the related concept corporate social irresponsibility (CSI), suffer from the single actor problem, where the corporation too easily becomes the exclusive focus of analysis. We advocate for a reinvigorated debate about mining and social responsibility in which the corporation is but one actor in the (ir)responsibility landscape.

Decarbonization, population disruption and resource inventories in the global energy transition.

We develop a novel approach to analysing decarbonisation strategies by linking global resource inventories with demographic systems. Our 'mine-town systems' approach establishes an empirical basis for examining the spatial extent of the transition and demographic effects of changing energy systems. The research highlights an urgent need for targeted macro-level planning as global markets see a decline in thermal coal and a ramp up of other mining commodities. Our findings suggest that ramping up energy transition metals (ETM) could be more disruptive to demographic systems than ramping down coal. The data shows asymmetry in the distribution of risks: mine-town systems within the United States are most sensitive to coal phase-out, while systems in Australia and Canada are most sensitive to ETM phase-in. A complete phase-out of coal could disrupt demographic systems with a minimum of 33.5 million people, and another 115.7 million people if all available ETM projects enter production.

Systemic IL-27 administration prevents abscess formation and osteolysis via local neutrophil recruitment and activation.

Interleukin-27 is a pleiotropic cytokine whose functions during bacterial infections remain controversial, and its role in patients with S. aureus osteomyelitis is unknown. To address this knowledge gap, we completed a clinical study and observed elevated serum IL-27 levels (20-fold higher, P < 0.05) in patients compared with healthy controls. Remarkably, IL-27 serum levels were 60-fold higher in patients immediately following septic death than in uninfected patients (P < 0.05), suggesting a pathogenic role of IL-27. To test this hypothesis, we evaluated S. aureus osteomyelitis in WT and IL-27Rα-/- mice with and without exogenous IL-27 induction by intramuscular injection of rAAV-IL-27p28 or rAAV-GFP, respectively. We found that IL-27 was induced at the surgical site within 1 day of S. aureus infection of bone and was expressed by M0, M1 and M2 macrophages and osteoblasts but not by osteoclasts. Unexpectedly, exogenous IL-27p28 (~2 ng·mL-1 in serum) delivery ameliorated soft tissue abscesses and peri-implant bone loss during infection, accompanied by enhanced local IL-27 expression, significant accumulation of RORγt+ neutrophils at the infection site, a decrease in RANK+ cells, and compromised osteoclast formation. These effects were not observed in IL-27Rα-/- mice compared with WT mice, suggesting that IL-27 is dispensable for immunity but mediates redundant immune and bone cell functions during infection. In vitro studies and bulk RNA-seq of infected tibiae showed that IL-27 increased nos1, nos2, il17a, il17f, and rorc expression but did not directly stimulate chemotaxis. Collectively, these results identify a novel phenomenon of IL-27 expression by osteoblasts immediately following S. aureus infection of bone and suggest a protective role of systemic IL-27 in osteomyelitis.

Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot.

Staphylococcus aureus osteomyelitis remains a very challenging condition; recent clinical studies have shown infection control rates following surgery/antibiotics to be ~60%. Additionally, prior efforts to produce an effective S. aureus vaccine have failed, in part due to lack of knowledge of protective immunity. Previously, we demonstrated that anti-glucosaminidase (Gmd) antibodies are protective in animal models but found that only 6.7% of culture-confirmed S. aureus osteomyelitis patients in the AO Clinical Priority Program (AO-CPP) Registry had basal serum levels (>10 ng/ml) of anti-Gmd at the time of surgery (baseline). We identified a small subset of patients with high levels of anti-Gmd antibodies and adverse outcomes following surgery, not explained by Ig class switching to non-functional isotypes. Here, we aimed to test the hypothesis that clinical cure following surgery is associated with anti-Gmd neutralizing antibodies in serum. Therefore, we first optimized an in vitro assay that quantifies recombinant Gmd lysis of the M. luteus cell wall and used it to demonstrate the 50% neutralizing concentration (NC50) of a humanized anti-Gmd mAb (TPH-101) to be ~15.6 µg/ml. We also demonstrated that human serum deficient in anti-Gmd antibodies can be complemented by TPH-101 to achieve the same dose-dependent Gmd neutralizing activity as purified TPH-101. Finally, we assessed the anti-Gmd physical titer and neutralizing activity in sera from 11 patients in the AO-CPP Registry, who were characterized into four groups post-hoc. Group 1 patients (n=3) had high anti-Gmd physical and neutralizing titers at baseline that decreased with clinical cure of the infection over time. Group 2 patients (n=3) had undetectable anti-Gmd antibodies throughout the study and adverse outcomes. Group 3 (n=3) had high titers +/- neutralizing anti-Gmd at baseline with adverse outcomes. Group 4 (n=2) had low titers of non-neutralizing anti-Gmd at baseline with delayed high titers and adverse outcomes. Collectively, these findings demonstrate that both neutralizing and non-neutralizing anti-Gmd antibodies exist in S. aureus osteomyelitis patients and that screening for these antibodies could have a value for identifying patients in need of passive immunization prior to surgery. Future prospective studies to test the prognostic value of anti-Gmd antibodies to assess the potential of passive immunization with TPH-101 are warranted.

Computational analysis of Lisfranc surgical repairs.

Ligamentous Lisfranc injuries cause debilitating pain and loss of function. Even small diastasis of this normally rigid joint after injury requires surgical treatment, but outcomes remain poor. Existing literature has compared the different surgical procedures using cadaveric models, but no approach has been recommended over others. This study uses a computational biomechanical approach consistent with a cadaveric study to evaluate the different procedures' ability to stabilize the Lisfranc joint without inducing secondary consequences. A validated rigid body model for the cadaver foot with a Lisfranc injury was extended to compare the stability of four different surgical repairs-three open reduction and internal fixation procedures with different hardware (cannulated screws, endobuttons, and screws with a dorsal plate) and primary arthrodesis with screws. Forces calculated from the rigid body model for 50% partial weight bearing provided boundary conditions for a finite element model of the surgical repairs. Comparing the different surgical procedures, the open reduction and internal fixation with screws and primary arthrodesis with screws showed the most stable postoperative Lisfranc joint. However, the use of cannulated screws for fixation showed regions of high stress that may be susceptible to breakage and also resulted in higher contact forces in joints adjacent to the surgery site. Endobuttons and dorsal plates did not restore sufficient stability. Since all procedures showed different points of concern that could impact outcomes, additional surgical approaches could be needed in the future. This study offers a standard protocol for benchmarking the new procedures against those currently used.

Low albumin level is more strongly associated with adverse outcomes and Staphylococcus aureus infection than hemoglobin A1C or smoking tobacco.

Postsurgical deep musculoskeletal infections are a major clinical problem in Orthopaedic Surgery. A serum-based nomogram, which can objectively risk-stratify patients, and aid surgeons in delineating infection risk associated with orthopedic surgical interventions, would be immensely helpful. Here, we constructed a multi-parametric nomogram based on serum anti-Staphylococcus aureus antibody responses, patient characteristics including demographics and standard clinical tests. This nomogram was formally tested in a prospective cohort study comparing 303 hospitalized patients with culture-confirmed S. aureus infection compared with a cohort of 223 healthy screened preoperative patients. Serum anti-S. aureus antibody responses, standard of care clinical tests, and patient demographic data were utilized to perform multivariate logistic regression analysis to quantify the presence of infection and adverse outcome using odds ratios (OR) and to assess predictive ability via area under the ROC curve (AUC). At enrollment, high anti-S. aureus IgG titers were predictive of infection. Remarkably, low serum albumin was found to be significantly associated with infection (OR = 479.963, 95% CI 61.59 - 3740.33, p < 0.0001) and this finding was surprisingly higher than BMI or HbA1c-associations. Combining all risk factors in the nomogram yielded a diagnostic AUC of 0.949 for predicting S. aureus infection. Our results indicate that a serum-based multi-parametric nomogram can be useful in diagnosing S. aureus infections, and importantly, malnourishment is significantly associated with these infections.

Electrochemistry from first-principles in the grand canonical ensemble.

Progress in electrochemical technologies, such as automotive batteries, supercapacitors, and fuel cells, depends greatly on developing improved charged interfaces between electrodes and electrolytes. The rational development of such interfaces can benefit from the atomistic understanding of the materials involved by first-principles quantum mechanical simulations with Density Functional Theory (DFT). However, such simulations are typically performed on the electrode surface in the absence of its electrolyte environment and at constant charge. We have developed a new hybrid computational method combining DFT and the Poisson-Boltzmann equation (P-BE) capable of simulating experimental electrochemistry under potential control in the presence of a solvent and an electrolyte. The charged electrode is represented quantum-mechanically via linear-scaling DFT, which can model nanoscale systems with thousands of atoms and is neutralized by a counter electrolyte charge via the solution of a modified P-BE. Our approach works with the total free energy of the combined multiscale system in a grand canonical ensemble of electrons subject to a constant electrochemical potential. It is calibrated with respect to the reduction potential of common reference electrodes, such as the standard hydrogen electrode and the Li metal electrode, which is used as a reference electrode in Li-ion batteries. Our new method can be used to predict electrochemical properties under constant potential, and we demonstrate this in exemplar simulations of the differential capacitance of few-layer graphene electrodes and the charging of a graphene electrode coupled to a Li metal electrode at different voltages.

Global Scan of Disruptions to the Mine Life Cycle: Price, Ownership, and Local Impact.

Criticality and supply risk models seek to address concerns of potential disruption to global metal supply. These models need to incorporate disruption events that arise from within the mining industry's market structure. In this paper, we review what we refer to as events of "mine life cycle disruption". These include project abandonments, premature closures, care and maintenance, and ownership changes. Life cycle disruptions not only cause production disruptions but also embed social and environmental risks in global metal markets. They arise from the highly variable business environment in which the resources sector operates. Changing commodity prices directly influence mining revenues and drive decisions on whether to halt or push forward a project. While some disruptions are involuntary and induced by external economic conditions, others are purposefully triggered by certain mining companies that use them to their advantage. We examine the frequency of these disruptions based on a contemporary global inventory of 35,000 mining projects and present the findings against recent developments in the research literature. We conclude that life cycle disruption events are an important consideration in balancing the demand for metals and the social and environmental impacts of mining and propose pathways for managing these events and their effects.

Computational analysis of the clinical presentation of a ligamentous Lisfranc injury.

Lisfranc injuries in the midfoot disrupt key arches of the foot which, if left untreated, can progress to pain, dysfunction, and arthritis. A clinical challenge is that 30-40% of Lisfranc injuries are missed in initial evaluations. The objective of this study was to explore different conditions of limb loading that could influence the biomechanics of the Lisfranc joint in a validated computational model. A computational model was created using SolidWorks software to represent the bones and soft tissues of the lower leg and foot. The model was compared to a cadaveric study of healthy and injured Lisfranc joints. The model was then used to simulate weight-bearing radiographs and evaluate how muscle activity and foot position impacted the diastasis of the Lisfranc joint, a key indicator used to diagnose Lisfranc injuries. The computational model was within one standard deviation of the cadaveric study in all measurements for the healthy and injured foot. When simulating weight-bearing radiographs, the presence of muscle activity or inversion/eversion resulted in less joint separation for the model with ligamentous Lisfranc injuries. While previous research has noted that weight-bearing radiographs provide better conditions to assess Lisfranc injuries than nonweight-bearing, this study suggests that in weight-bearing radiographs both altering the position of the foot, possibly due to pain, and the active contraction of the extrinsic flexor muscles can obfuscate indications of a Lisfranc injury.

Distinct expression trend of signature antigens of Staphylococcus aureus osteomyelitis correlated with clinical outcomes.

The major limitations of clinical outcome predictions of osteomyelitis mediated by Staphylococcus aureus (S. aureus) are not specific and definitive. To this end, current studies aim to investigate host immune responses of trend changes of the iron-regulated surface determinant (Isd) of IsdA, IsdB, IsdH, cell wall-modifying proteins of amidase (Amd) and glucosaminidase (Gmd), and secreted virulence factor of chemotaxis inhibitory protein S. aureus (CHIPS) and staphylococcal complement inhibitor (SCIN) longitudinally to discover their correlationship with clinical outcomes. A total of 55 patients with confirmed S. aureus infection of the long bone by clinical and laboratory methods were recruited for the study. Whole blood was collected at 0, 6, 12 months for the serum that was used to test IsdA, IsdB, IsdH, Gmd, Amd, CHIPS, and SCIN using a customized Luminex assay after clinical standard care parameters were collected. The patients were then divided into two groups: (1) infection controlled versus (2) adverse outcome based on clinical criteria for statistical analysis. We found that standard clinical parameters were unable to distinguish therapeutic outcomes. Significant overexpression of all antigens was confirmed in infection patients at 0-, 6-, and 12-month time points. A distinct expression trend and dynamic changes of IsdB, Amd, Gmd, and CHIPS were observed between infection controlled and adverse outcome patients, while the IsdA, IsdH, SCIN remained demonstrated no statistical significance. We conclude that dynamic changes of specific antigens could predict clinical outcomes of S. aureus osteomyelitis. Clinical Relevance: The trend changes of host immune responses to S. aureus specific antigens of IsdB, Gmd, Amd, and CHIPS could predict clinical outcomes of S. aureus osteomyelitis.

Serum antibodies against Staphylococcus aureus can prognose treatment success in patients with bone infections.

Prognosing life-threatening orthopedic infections caused by Staphylococcus aureus remains a major clinical challenge. To address this, we developed a multiplex assay to assess the humoral immune proteome against S. aureus in patients with musculoskeletal infections. We found initial evidence that antibodies against some antigens (autolysins: Amd, Gmd; secreted immunotoxins: CHIPS, SCIN, Hla) were associated with protection, whereas antibodies against the iron-regulated surface determinant (Isd) proteins (IsdA, IsdB, IsdH) were aligned with adverse outcomes. To formally test this, we analyzed antibody levels and 1-year clinical outcomes of 194 patients with confirmed S. aureus bone infections (AO Trauma Clinical Priority Program [CPP] Bone Infection Registry). A staggering 20.6% of the enrolled patients experienced adverse clinical outcomes (arthrodesis, reinfection, amputation, and septic death) after 1-year. At enrollment, anti-S. aureus immunoglobulin G (IgG) levels in patients with adverse outcomes were 1.35-fold lower than those in patients whose infections were successfully controlled (p < 0.0001). Overall, there was a 51%-69% reduction in adverse outcome risk for every 10-fold increase in initial IgG concentration against Gmd, Amd, IsdH, CHIPS, SCIN, and Hla (p < 0.05). Notably, anti-IsdB antibodies remained elevated in patients with adverse outcomes; for every 10-fold change in the ratio of circulating anti-Isd to anti-Atl IgG at enrollment, there was a trending 2.6-fold increased risk (odds ratio = 2.555) of an adverse event (p = 0.105). Moreover, antibody increases over time correlated with adverse outcomes and decreases with positive outcomes. These studies demonstrate the potential of the humoral immune response against S. aureus as a prognostic indicator for assessing treatment success and identifying patients requiring additional interventions.

Governing deep sea mining in the face of uncertainty.

Progress towards deep sea mining (DSM) is driven by projected demands for metals and the desire for economic development. DSM remains controversial, with some political leaders calling for a moratorium on DSM pending further research into its impacts. This paper highlights the need for governance architectures that are tailored to DSM. We conceptualise DSM as a type of complex orebody, which encompasses the breadth of environmental, social and governance (ESG) risks that make a mineral source complex. Applying a spatial overlay approach, we show that there are significant data gaps in understanding the ESG risks of DSM. Such uncertainties are compounded by fact that there are no extant commercial DSM projects to function as a precedent - either in terms of project design, or the impacts of design on environment and people. Examining the legislation of the Cook Islands and International Seabed Authority, we demonstrate how regulators are defaulting to terrestrial mining governance architectures, which cannot be meaningfully implemented until a fuller understanding of the ESG risk landscape is developed. We argue that DSM be approached as a distinct extractive industry type, and governed with its unique features in frame.

A Biomechanical Comparison of the Effect of Baseplate Design and Bone Marrow Fat Infiltration on Tibial Baseplate Pullout Strength.

BACKGROUND: Early clinical results of a new total knee arthroplasty (TKA) implant design show promise for improved outcomes and patellofemoral function scores. However, reports of early tibial component-cement interface debonding requiring revision have been published. This study investigated the biomechanical properties of three different tibial baseplates to understand potential causes of failure. METHODS: PFC Sigma (control), Attune (1st generation) and Attune S+ (2nd generation) tibial baseplates were implanted into 4th generation sawbone tibia models using a standardized technique. Three of each baseplate were cemented with and without additional bovine bone marrow fat. All models were tested to failure with measured axial distraction force. Implant type, presence or absence of bovine marrow and load to failure were all recorded and compared. Two-way ANOVA followed by post-hoc pairwise comparisons were used to determine statistical significance, which was set to P < .05. RESULTS: The 2nd generation tibial baseplates required significantly more force to failure. The presence of bovine marrow significantly reduced the pullout force of the implant designs overall. No significant difference was detected between the 1st generation and control baseplates. Failure mode for each model was also noted to be different irrespective of the presence or absence of bone marrow fat. CONCLUSION: The 2nd generation baseplates required significantly more force to failure compared with older designs. The presence of bone marrow during cementation of a tibial base plate significantly decreased axial pullout strength of a tibial baseplate in this laboratory model. All 1st generation baseplates exhibited debonding at the cement-implant interface.

The social and environmental complexities of extracting energy transition metals.

Environmental, social and governance pressures should feature in future scenario planning about the transition to a low carbon future. As low-carbon energy technologies advance, markets are driving demand for energy transition metals. Increased extraction rates will augment the stress placed on people and the environment in extractive locations. To quantify this stress, we develop a set of global composite environmental, social and governance indicators, and examine mining projects across 20 metal commodities to identify the co-occurrence of environmental, social and governance risk factors. Our findings show that 84% of platinum resources and 70% of cobalt resources are located in high-risk contexts. Reflecting heightened demand, major metals like iron and copper are set to disturb more land. Jurisdictions extracting energy transition metals in low-risk contexts are positioned to develop and maintain safeguards against mining-related social and environmental risk factors.

Lack of Humoral Immunity Against Glucosaminidase Is Associated with Postoperative Complications in Staphylococcus aureus Osteomyelitis.

BACKGROUND: Glucosaminidase (Gmd) is known to be a protective antigen in animal models of Staphylococcus aureus osteomyelitis. We compared the endogenous anti-Gmd antibody levels in sera of patients with culture-confirmed S. aureus bone infections to their sera at 1 year after operative treatment of the infection. METHODS: A novel global biospecimen registry of 297 patients with deep-wound culture-confirmed S. aureus osteomyelitis was analyzed to assess relationships between baseline anti-Gmd serum titers (via custom Luminex assay), known host risk factors for infection, and 1-year postoperative clinical outcomes (e.g., infection control, inconclusive, refracture, persistent infection, septic nonunion, amputation, and septic death). RESULTS: All patients had measurable humoral immunity against some S. aureus antigens, but only 20 patients (6.7%; p < 0.0001) had high levels of anti-Gmd antibodies (>10 ng/mL) in serum at baseline. A subset of 194 patients (65.3%) who completed 1 year of follow-up was divided into groups based on anti-Gmd level: low (<1 ng/mL, 54 patients; 27.8%), intermediate (<10 ng/mL, 122 patients; 62.9%), and high (>10 ng/mL, 18 patients; 9.3%), and infection control rates were 40.7%, 50.0%, and 66.7%, respectively. The incidence of adverse outcomes in these groups was 33.3%, 16.4%, and 11.1%, respectively. Assessing anti-Gmd level as a continuous variable showed a 60% reduction in adverse-event odds (p = 0.04) for every tenfold increase in concentration. No differences in patient demographics, body mass index of >40 kg/m, diabetes status, age of ≥70 years, male sex, Charlson Comorbidity Index of >1, or Cierny-Mader host type were observed between groups, and these risk factors were not associated with adverse events. Patients with low anti-Gmd titer demonstrated a significant 2.68-fold increased odds of adverse outcomes (p = 0.008). CONCLUSIONS: Deficiency in circulating anti-Gmd antibodies was associated serious adverse outcomes following operative treatment of S. aureus osteomyelitis. At 1 year, high levels of anti-Gmd antibodies were associated with a nearly 3-fold increase in infection-control odds. Additional prospective studies clarifying Gmd immunization for osteomyelitis are needed. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Invisibility and the extractive-pandemic nexus.

The Covid-19 pandemic is reshaping the world economy. Headline news stories depict mining companies as a stabilising force: supporting the flow of resources to keep the economy moving, and contributing to local welfare initiatives for communities in crisis. We argue that this narrative masks important details about the local conditions where mining companies operate. The issues at the company-community interface are typically invisible to distant audiences. While travel restrictions are necessary to limit community-spread, these constraints push interfaces in mining communities further into the unknown. The effects of the global pandemic will be far reaching. Scholarship is needed to understand the dynamics of mining in the time of Covid-19 and to place present impacts, actions, and decisions in their proper historical context.

Evolving concepts in bone infection: redefining "biofilm", "acute vs. chronic osteomyelitis", "the immune proteome" and "local antibiotic therapy".

Osteomyelitis is a devastating disease caused by microbial infection of bone. While the frequency of infection following elective orthopedic surgery is low, rates of reinfection are disturbingly high. Staphylococcus aureus is responsible for the majority of chronic osteomyelitis cases and is often considered to be incurable due to bacterial persistence deep within bone. Unfortunately, there is no consensus on clinical classifications of osteomyelitis and the ensuing treatment algorithm. Given the high patient morbidity, mortality, and economic burden caused by osteomyelitis, it is important to elucidate mechanisms of bone infection to inform novel strategies for prevention and curative treatment. Recent discoveries in this field have identified three distinct reservoirs of bacterial biofilm including: Staphylococcal abscess communities in the local soft tissue and bone marrow, glycocalyx formation on implant hardware and necrotic tissue, and colonization of the osteocyte-lacuno canalicular network (OLCN) of cortical bone. In contrast, S. aureus intracellular persistence in bone cells has not been substantiated in vivo, which challenges this mode of chronic osteomyelitis. There have also been major advances in our understanding of the immune proteome against S. aureus, from clinical studies of serum antibodies and media enriched for newly synthesized antibodies (MENSA), which may provide new opportunities for osteomyelitis diagnosis, prognosis, and vaccine development. Finally, novel therapies such as antimicrobial implant coatings and antibiotic impregnated 3D-printed scaffolds represent promising strategies for preventing and managing this devastating disease. Here, we review these recent advances and highlight translational opportunities towards a cure.

Source Risks As Constraints to Future Metal Supply.

Rising consumer demand is driving concerns around the "availability" and "criticality" of metals. Methodologies have emerged to assess the risks related to global metal supply. None have specifically examined the initial supply source: the mine site where primary ore is extracted. Environmental, social, and governance ("ESG") risks are critical to the development of new mining projects and the conversion of resources to mine production. In this paper, we offer a methodology that assesses the inherent complexities surrounding extractives projects. It includes eight ESG risk categories that overlay the locations of undeveloped iron, copper, and aluminum orebodies that will be critical to future supply. The percentage of global reserves and resources that are located in complex ESG contexts (i.e., with four or more concurrent medium-to-high risks) is 47% for iron, 63% for copper, and 88% for aluminum. This work contributes to research by providing a more complete understanding of source level constraints and risks to supply.